Toward a full characterization of nucleic acid components in aqueous solution: simulations of nucleosides

The eight nucleoside constituents of nucleic acids were simulated for 50 ns in explicit water with molecular dynamics. This provides equilibrium populations of the torsional degrees of freedom, their kinetics of interconversion, their couplings, and how they are influenced by water. This is important, given that a full and quantitative characterization of the nucleosides in aqueous solution by experimental means has been elusive, despite immense efforts in that direction. It is with the anti/syn equilibrium that the simulations are most complementary to experiment, by accessing directly the influence of the sugar type, sugar pucker, and base on the anti/syn populations. The glycosidic torsion distributions in the anti conformation are strongly affected by water and depart from the corresponding X-ray modal values and the associated energy minima in vacuo. Water also preferentially stabilizes some sugar conformations, showing that potential energies in vacuo are not sufficient to understand the nucleosides. Deoxythymidine (but not other pyrimidines) significantly populates the syn orientation. Guanine favors the syn orientation more than adenine. The ribose favors the syn orientation significantly more than the deoxyribose. The NORTH pucker coexists with the syn conformers. A hydrogen bond is frequently formed between the 5'-OH group and the syn bases, despite competition by water. The rate of the anti/syn transitions with purines is on the nanosecond time scale, confirming a long held assumption underpinning the interpretation of ultrasonic relaxation studies. Therefore, our knowledge of the structure and dynamics of nucleosides in solvent is only limited by the accuracy of the potential used to simulate them, and it is shown that such simulations provide a distinct and unique test of nucleic acid force fields. This confirmed that the widely distributed CHARMM27 force field is, overall, well-balanced with a particularly good representation of the ribose. Specific improvements, however, are suggested for the deoxyribose and torsion gamma.